[Application of imatinib plus Hyper-CVAD chemotherapy regimen in patients with Ph chromosome positive acute lymphocytic leukemia].

OBJECTIVE: To report the efficacy and safety of imatinib plus Hyper-CVAD chemotherapy regimen in the treatment of patients with ph chromosome positive acute lymphocytic leukemia (Ph(+)ALL). METHODS: A sequential 2-year and 8-cycle treatment of imatinib plus Hyper-CVAD (A/B program) was administrated in 18 Ph(+)ALL patients treated at our hospital since January 2005 to January 2010. And another 18 Ph(+)ALL patients undergoing no allogeneic hematopoietic stem cell transplantation were selected as controls. RESULTS: Among 18 patients on chemotherapy, their average age was 33.1 years, the total response rate 100% following induction chemotherapy and the median survival 28.8 (8.0 - 60.0) months. And the 1-, 2- and 3-year overall survival rates were 77.8%, 72.2% and 66.7% respectively. In control patients, the response rate following induction chemotherapy was 100% and the median survival 22.5 (4.0 - 58.0) months. And the 1-, 2- and 3-year overall survival rates were 66.7%, 55.6% and 50.0% respectively. A recent follow-up showed that 5 patients (27.8%) died from relapse in the chemotherapy group and 4 (22.2%) in the control group. The overall deaths were 6 (33.3%) in the chemotherapy group and 9 (50.0%) in the control group. CONCLUSION: Imatinib plus Hyper-CVAD chemotherapy regimen is associated with significantly improved survival rates. Superior to allogeneic hematopoietic stem cell transplantation, it offers a prolonged median response time and survival time in Ph(+)ALL patients.

[Clinical Analysis of 41 Patients with Burkitt's lymphoma].

OBJECTIVE: To summarize the clinical characteristics of Burkitt's lymphoma. METHODS: Clinical data of 41 Burkitt's lymphoma patients, treated from Jannuary 2009 to June 2014 in Chinese PLA General Hospital, were analyzed retrospectively. RESULTS: Out of the 41 patients, 33 were males and 8 were females, with a median age of 13 (range, 1-67), 18 cases (43.9%) were in Ann Arbor stage I/II, and 23 cases (56.1%) were in stage III/IV. The commonest pathologicalal sites were head and neck (23 cases, 56.1%), and then the abdominal (41.5%), bone marrow (22.0%) and central nervous system (22.0%) could also be involved, while 7 cases (17.1%) were patients transformed into acute lymphocytic leukemia-type L3, 18% cases (3/16) were infected by EBV and 29.9% cases (6/38) were infected by HBV, 29 cases were treated with chemotherapy, their overal remission rate was 93.1(27/29 cases), 2-year overall survival rate(OS) was 83.3%(10/12 cases); 13 cases were treated with rituximab, their remission rate was 92.3%(12/13 cases), and 2-year OS was 66.7%(4/6 cases). CONCLUSION: The 41 cases are more similar to the sporadic Burkitt's lymphoma, but the median age of its occurence is more younger, while the most common pathological sites are head and neck, and the short-term and high intensive chemotherapy with rituximab can obviously elevate remission rate for adult patients and prolong their survival time.

A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells.

AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.

Demethylating agent decitabine induces autologous cancer testis antigen specific cytotoxic T lymphocytes in vivo.

BACKGROUND: Cancer testis antigens (CTAs) are a novel group of tumor associated antigens. Demethylating agent decitabine was reported to be able to up-regulate CTAs through its hypomethylation mechanism, thus enhance the immunogenicity of leukemia cells. However, few researches have ever focused on the questions that whether this immunostimulatory effect of decitabine could induce autologous CTA specific cytotoxic T lymphocytes (CTLs) in vivo, and if so, whether this effect contributes to disease control. In this study, we aimed to show that decitabine could induce specific autologous CTLs against some mouse CTAs in leukemia cells in vitro and in vivo. METHODS: Several mouse CTAs were screened by RT-PCR. CTL specific to one of the CTAs named P1A was detected and sorted by P1A specific dimer by flow cytometry. The activity of specific CTLs was measured by real time RT-PCR. RESULTS: We firstly screened expression of some CTAs in mouse leukemia cells before and after decitabine treatment and found that decitabine treatment did up-regulate expression of many CTAs. Then we measured the CTLs' activity specific to a mouse CTA P1A in vivo and showed that this activity increased after decitabine treatment. Finally, we sorted these in vivo induced P1A specific CTLs by flow cytometry and demonstrated their cytotoxicity against decitabine treated leukemia cells. CONCLUSIONS: Our study showed the autologous immune response induced by decitabine in vivo. And more importantly, we firstly proved that this response may contribute to disease control. We believe that this immunostimulatory effect is another anti-cancer mechanism of decitabine, and this special effect would inspire new applications of decitabine in the field of leukemia treatment in the future.

Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.